Evaluation of the Radiochemical Purity of Technetium-99m Radiopharmaceuticals: A Decade of Experience in an Accredited Laboratory

INTRODUCTION. The most important quality indicators of a radiopharmaceutical (RPh) are its radiochemical purity (RCP) or radiochemical impurity content (RCI), the values of which are standardized. Mandatory control testing of lyophilisates to assess composition, authenticity, apyrogenicity, and sterility is guaranteed by the manufacturer. Evaluation of the technetium-99m labeling process for lyophilisates, which can be influenced by numerous factors, is usually the responsibility of the end user. The methods presented in quality regulatory documents were developed in the 1970s and 1980s, and some of them require adjustment due to the upgrading of measurement instrumentation and the emergence of new materials.

AIM. To summarize the 10-year experience (2015–2025) of an accredited testing laboratory by analyzing the quality control results of ^99mTc-RPhs routinely used in clinical practice, to adjust existing analytical methods specified in manufacturers’ quality documents, and to develop new ones.

MATERIALS AND METHODS. Quality control of technetium-99m radiopharmaceuticals was performed using the most significant parameters, RCP/RCI, following the methods presented in the approved quality documents of the manufacturers. The radiopharmaceuticals were prepared from lyophilisates and eluate (Na^99mTcO₄ solution) from ⁹⁹Mo/^99mTc generators of the GT-2M, GT-4K, and GT-5K types.

RESULTS. During the 10 years of operation, the accredited laboratory tested 1106 radiopharmaceuticals. Analytical methods for determining RCP/RCI based on thinlayer chromatography (TLC) were identified and tested for the radiopharmaceuticals “Macrotech, ^99mTc,” “Bromezida, ^99mTc,” and “Pentatech, ^99mTc,” replacing the previously used filtration and high-voltage agarose gel electrophoresis methods. For the radiopharmaceutical “Technemek, ^99mTc,” a chromatographic method was tested instead of determining the radiochemical composition indicator. This method allows simultaneous determination of the technetium-99m complex with dimercaptosuccinic acid (retardation factor, R_f 0.45–0.70), free Na^99mTcO₄ (R_f 0.9–1.0) and hydrolyzed reduced technetium-99m (R_f 0–0.15).

CONCLUSIONS. Of the total number of radiopharmaceuticals tested over the 10-year period, only a limited number of radiopharmaceuticals (3.2%) had an RCP below the acceptable level. The advantages of the proposed methods lie in the simplification of the analytical procedures, which will allow their use in a medical facility immediately before administration of the radiopharmaceutical to the patient, as well as reliable determination of the most important quality indicator of the radiopharmaceutical (RCP), which is responsible for accumulation in the target organ. The developed methods can be proposed for inclusion in draft pharmacopeial monographs and to the manufacturers of lyophilisates for their incorporation into quality regulatory documents.

1. Haleem RM, Salem MY, Fatahallah FA, Abdelfattah LE. Quality in the pharmaceutical industry - A literature review. Saudi Pharm J. 2015; 23(5):463-9. doi: 10.1016/j.jsps.2013.11.004.

2. Grangeia HB, Silva C, Paulo Simões S, Reis MS. Quality by Design in Pharmaceutical Manufacturing: a systematic review of current status, challenges and future perspectives. European Journal of Pharmaceutics and Biopharmaceutics. 2019; 1-41. doi: 10.1016/j.ejpb.2019.12.007.

3. Zolle I. Technetium-99m pharmaceuticals: Preparation and quality control in nuclear medicine. Berlin Heidelberg: Springer; 2007.p. 123-43

4. Maioli C, Luciniani G, Strinchini A, et al. Quality control on radiochemical purity in Technetium99m radiopharmaceuticals labelling: three years of experience on 2280 procedures. Acta Biomed. 2017; 88(1):49-56.

5. Ullah H, Ahmad I, Khattak MR, et al. Evaluation of radiochemical purities of routinely used radiopharmaceuticals: Three years’ experience of a single institute. Iran J Nucl Med. 2019; 27(1):19-25. doi: 10.18502/irjnm.v27i1.970.

6. Ballinger JR, Blower PJ. Radiochemical purity testing of 99mTc-labelled radiopharmaceuticals: how much is enough? Nucl Med Commun. 2011; 32(9):761-3.

7. Kovaleva EL, Zolotov YuA, Somov DV. Quality assurance of medicines: main scientific approaches and control methods. Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. Regulatory Research and Medicine Evaluation. 2023;13(3):368–375 (In Russ.). https://doi.org/10.30895/1991-2919-2023-13-3-368-375.

8. Thota P, Thota A, Pandey MK, Sarma P, et al. A comparative study of pharmacopoeial quality standards and regulations of radiopharmaceuticals. Indian J Nucl Med. 2021;36:153-62. doi: 10.4103/ijnm.ijnm_222_20.

9. Molavipordanjani S, Hosseinimehr SJ. Fundamental concepts of radiopharmaceuticals quality controls. Pharm Biomed Res. 2018;4(3): 1-8.

10. Ekinci М, Santos-Oliveira R, İlem-Özdemir D. Quality assurance and quality control of radiopharmaceuticals: an overview. J. Fac. Pharm. Ankara. 2022; 46(3): 1044-1063.

11. Islam S, Azim M, Uddin J, et al. Routine Radiochemical Quality Control of 99mTc eluate and 99mTc-Labeled Radiopharmaceuticals. Bangladesh J. Nucl. Med. 2023; 26(2):193-197. doi: https://doi.org/10.3329/bjnm.v26i2.71493.

12. Mang'era K, Wong D, Douglas D, et al. Evaluation of alternative rapid thin layer chromatography systems for quality control of technetium-99m radiopharmaceuticals. Appl Radiat Isot. 2014; 86: 57- 62.

13. Küçüker KA, Güney IB; Aikimbaev K. et al. Unexpected Hepatic Uptake of Tc-99m-MAA in Lung Perfusion Scintigraphy in a Patient with End-stage Renal Disease. Mol. Imaging Radionucl. Ther. 2019; 28: 27–9.

14. Bajc M, Neilly JB, Miniati M. et al. EANM guidelines for ventilation/perfusion scintigraphy. Eur. J. Nucl. Med. Mol. Imaging. 2009; 36: 1356–70.

15. Jensen SB, Meyer LS, Nielsen NS, Nielsen SS. Issues with the European Pharmacopoeia Quality Control Method for 99mTc-Labelled Macroaggregated Albumin. Molecules. 2022; 27: 1-9. https://doi.org/10.3390/molecules27133997.